2-tertiaryamino-6-(dialkylaminoalkoxy)-benzothiazoles and process for their manufacture



Patented Dec. 18, 1951 2-TERTIARYAMINO-61L(DIALKYLAMINOALK-OXY)-BENZOTHIAZOLES AND PROCESS FOR THEIR MANUFACTURE Norbert Steiger,Nutley, and Oscar Keller, Clifton, N. J., assignors to Hoffmann-La RocheInc., Nutley, N. J .,1 a corporation of New Jersey No Drawing.Application March 2, 1949, Serial No. 79,316

The present invention relates to new derivatives of benzothiazoles andto the process for their manufacture. More particularly the in- 12Claims. (Cl. 260293.4)

vention relates to 2-tertiaryamino-6-(dialkylaminoalkoxy)-benzothiazoles and acid addition salts thereof. The new compoundsin'ithe form of the free base can be represented by the followingformula:

S NIL.

In the above formula, Z stands for a radical of a secondary amine, forexample, pi'peridino, morpholino, and tetrahydroquinolino, and

wherein R1 and R2 may be the same or difierent and stand for a loweralkyl radical such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tertiary-butyl, amyl, isoamyl, and the like; an

aryl radical, as for example, phenyl, or an aralkyl radical, such asbenzyl. The letter n stands for a number from 2-5, and the group CnH2nincludes alkylene, branched alkylene, and alkylidene radicals. i

The new compounds are characterized by their activity against fungi,more particularly against pathogenic and plant fungi.

According to the present invention, the Z-tertiaryamino 6(dialkylaminoalkoxy) 4 benzothiazoles can be prepared by reacting aZ-tertiaryamino-6-hydroxybenzothiazole in the form of its alkali metalsalts, as for example, the sodium, potassium or lithium salts, with adialkylaminoalkyl halide, as for example, a dialkylaminoethane chloride,dialkylaminopropane chloride, dialkylaminobutane chloride,dialkylaminoheptane chloride, 2-chloro-1-dialkylamino-propane,1-chloro-2,2-dimethy13-dia1kylamino propane, and the like. The reactionis preferably carried out in the presence of an organic solvent ordiluent, as for example, chlorbenzene, toluene, xylene, and the like.The 2-tertiaryamino-6-(di alkylaminoalkoxy)-benzothiazole can berecovered from the reaction medium as the free base by removing theorganic solvent; or as the acid addition salts thereof, for example, asthe hydrochloride or hydrobromide, by passing HCl or HBr into thereaction medium. The free bases are oils, soluble in the usual organicsolvents, insoluble in water, but soluble in dilute acids. Thehydrochlorides are soluble in water, methanol and ethanol.

The free bases readily yield acid addition salts with both organicand'inorganic acids. Thus, by treating the bases with an equivalentamount of an acid, as for example, hydrochloric, hydrobromic, sulfuric,phosphoric, nitric, acetic, propionic, caprylic, undecylenic, tartaric,and citric acids, the corresponding acid addition salts of theZ-tertiaryamino 6 (dia1kylaminoalkoxy)- benzothiazoles are obtained.

PREPARATION OF 2-TERTIARYAMINO-6- HYDROXY-BENZOTHIAZOLES The2-tertiaryamino-6hydroxy-benzothiazoles employed as starting materialscan be readily prepared from the correspondingZ-tertiaryamino-6-alkoxy-benzothiazoles by hydrolysis with aqueoushydrobromide solution or with aluminum chloride in a suitable solvent,such as chlorben'zene.

The method of preparing the Z-tertiaryamino- G-hydroxy-benzothiazoles isillustrated by the following examples:

EXAMPLE A 6 -hydroxy-2-morphoZyZ-benzothiazole 66 grams of6-ethoxy-2-morpholyl-benzothiazole were suspended in 3'75 cc. ofchlorbenzene, and 70 grams of aluminum chloride were added in portionswith stirring. The mixture was then refluxed at -l35 C. for three hours.The chlorbenzene layer was decanted and the thick residue was decomposedwith ice. 15 cc. of concentrated (37 per cent) hydrochloric acid wereadded, the chlorbenzene was returned to the reaction vessel and thewhole was steam distilled. The aqueous residue was cooled at 4 0.,whereupon a precipitate was obtained. This was purified by dissolving inhot water and reprecipitated with sodium acetate to obtain theS-hydroxy-Z- morpholyl-benzothiazole which on crystallization fromaqueous alcohol had a M. P. of 192-194" C.

EXAMPLE B G-hydroxy-Z- (1 ,2,3,4-tetrahydroqui'nolyl benzothiazole 19grams of 6ethoxy-2(l,2,3,4 tetrahydroquinolyD-benzothiazole weresuspended in cc. of chlorbenzene, and 20 grams of aluminum chloride wereadded in portions. The mixture was refluxed at l30135 C. for four hours.The chlorbenzene was decanted and the residue was decomposed with iceand 20 cc. of concentrated hydrochloric acid. The chlorbenzene wasreturned to the reaction vessel and the whole was steam distilled. Theaqueous residue was treated with 100 grams of sodium chloride and cooledat 4 C. The yellow precipitate was filtered off, dissolved in dilutealkali and reprecipitated with hydrochloric acid and sodium acetate, toyield the above-entitled benzothiazole, which on crystallization fromalcohol had a M. P. of 2l8220 C.

The 6 ethoxy-2-(1,2,3,4-tetrahydroquinolyl) benzothiazole was preparedin the following manner:

19.5 grams of p-ethoxy-phenyl-isothiocyanate were condensed with 14grams of 1,2,3,4-tetrahydroquinoline in 100 cc. of ligroin by refluxingon a steam bath for three hours. The l-(p-ethoxyphenyl-thiocarbamyl)1,2,3,4 tetrahydroquinoline formed was brominated with 16 grams ofbromine in 125 cc. of chloroform by refluxing for three hours on a steambath. After distilling off the solvent, the hydrobromide of G-ethoxy- 2-(1,2,3,4-tetrahydroquinolyl) -benzothiazole thus obtained wascrystallized from alcohol, M. P. 208-210 C. The hydrobromide wasconverted to the free base by dissolving it in hot dilute hydrochloricacid and precipitating with solid sodium acetate. Crystallized fromethanol the free base had a M. P. of 143-145 C.

EXAMPLE C G-hydroxy-2-dibutylamino-benzothiazole 36 grams of6-ethoxy-Zdibutylamino-benzothiazole were suspended in 200 cc. ofchlorbenzene, and 34 grams of aluminum chloride were added in portions.The mixture was refluxed at 130-135 C. for four hours. After cooling,the mixture was slowly added to 25 cc. of concentrated hydrochloric acidand ice with cooling. The chlorbenzene was steam distilled and theaqueous residue was treated with 200 grams of sodium chloride. Aftercooling at 4 C., the solid was dissolved in dilute alkali, the solutionacidified with hydrochloric acid and treated with sodium acetate toprecipitate the free base. The product was crystallized from aqueousalcohol.

EXAMPLE D 6-hydromy-2-dimethylamino-ben2othiazole 30 grams of6-ethoxy-2-dimethylamino-benzothiazole were heated with300 cc. of 48 percent hydrobromic acid on a steam bath under reflux for 24 hours. Thereaction mixture while still hot was diluted with 1,000 cc. of water.The solution was made alkaline to phenolphthalein with 40 per centsodium hydroxide and after stirring for hour was filtered with charcoal.The filtrate was made acid to congo with concentrated hydrochloric acidand cooled at 4 C. The crystalline solid that separated was filteredoff, washed with ice water and dried at room temperature in vacuo. The6-hydroxy-2-dimethylamino-benzothiazole hydrobromide thus obtained oncrystallizing from alcohol had a M. P. of 245246 C.

By sludging the hydrobromide with an excess of sodium acetate solutionto 60 C. until congo indicator no longer showed a bluish stain, andfiltering followed by drying the residue, there was obtained the freebase of G-hydroxy-Z-dimethylamino-benzothiazole.

EXAMPLE E fi-hydroxy-z-piperidyl-benzothiazole By employing 93 grams of6-ethoxy-2-piperidyl-benzothiazole and grams of aluminum chloride andproceeding as in Example A, there was obtained6-hydroxy-2-piperidyl-benzothiazole, M. P. 217-219 C.

EXAMPLE F G-hydroxy-Z-methylphenylamino-beneothiazole By employing 30grams of 6-ethoxy-2-methylphenylamino-benzothiazole and 32 grams ofaluminum chloride, and proceeding as in Example A, there was obtained6-hydroxy-2-methylphenylamino-benzothiazole, M. P. 1'71-1'I4 C.

The 6-ethoxy-2-methylphenylamino-benzothia zole was prepared in thefollowing manner:

54 grams of p-ethoxy-phenyl-isothiocyanate were condensed with 36 gramsof methyl aniline in 200 cc. of ligroin by refluxing on a steam bath.The p ethoxy phenyl methylphenyl-thiourea which formed was obtained byconcentrating the reaction mixture, then diluting with ether.

75.5 grams of the thiourea were brominated with 24 grams of bromine in350 cc. of chloroform by refluxing on a steam bath for four hours. Afterdistilling off the solvent, the residue obtained was diluted with ether.The 6-ethoxy-2methylphenylamino benzothiazole hydrobromide thus obtainedhad a M. P. of 184-186 C. when crystallized from ethanol-ether.

The hydrobromide was converted to the free base by extraction withdilute hydrochloric acid and precipitating with sodium acetate. The freebase on crystallization from ethanol had a M. P. of 118-120 C.

EXAMPLE G G-hydroxy-Z-methylbenzylamino-benzothiazole By employing 25grams of 6-ethoxy-methylbenzylamino-benzothiazole and 100 cc. of 48 percent hydrobromic acid and proceeding as in Example D, there was obtained6-hydroxy-2-methylbenzylamino-benzothiazole, M. P. 169 C.

The G-ethoxy 2 methylbenzylamino-benzothiazole was obtained in thefollowing manner:

141 grams of 6-ethoXy-benzothiazole-2-sodium sulfonate were condensedwith 200 grams of methylbenzylamine in 500 cc. of alcohol and 225 cc. ofwater, in the presence of 30 grams of zinc chloride in a closed vesselat C. On the dilution of the reaction mixture with water, fi-ethoxy- 2methylbenzylamino benzothiazole was obtained. O-n crystallization fromaqueous ethanol, it had a M. P. of 76-80 C.

PREPARATION OF 2-TERTIARYAMINO-6- (DIALKYLAMINOALKOXY) BENZOTHIA- ZOLESThe following examples will serve to ilustrate the preparation of the2-tertiaryamino-6-(dialkylaminoalkoxy) -benzothiazoles.

EXAMPLE 1 Z-dimethylamino-G- (fi-diethylamz'noethomy) benzothiazoledihydrochloride 19.4 grams of 2-dimethylamino6-hydroxy-benzothiazoie (M.245 C.) were sludged in a 500 cc. three-necked flask with 250 cc. ofchlorbenzene. Then 4.4 grams of sodium hydroxide flakes were added andthe mixture heated with agitation to 90 C. 4 cc. of water were droppedin, and the mixture then heated slowly to the boil while about 500 cc..of the water-containing chlorbenzene were distilled off. 50 cc. of drychlorbenzene were then added and the distillation was continued untilabout 30 cc. of the chlorbenzene were distilled off. The residue was thesodium salt of thiazole in chlorbenzene. To the residue were added at 90C., 15 grams of fresh distilled 1-diethylamino-2-chloro-ethane. Themixture was then refluxed at 133 C. for three hours, then cooled to 35C. 75 cc. of water and 5 cc. of (40 per cent by volume) sodium hydroxidesolution were added and the mixture stirred for one hour. Thechlorbenezene layer which contained the reaction product was separatedfrom the aqueous layer in a separatory funnel. The chlorbenzene solutionwas then dried with sodium sulfate for twelve hours. It was thenfiltered and HCl gas was passed into the chlorbenzene solution untilsaturated, while cooling and stirring. The dihydrochloride precipitatedas a white crystalline, sandy powder. The precipitate was filtered andwashed on the funnel with benzene and finally washed with ether. Thefilter cake was dried at 80-90 C. The2-dimethylamino-6-(B-diethylaminoethoxy) benzothiazole dihydrochloridethus obtained is a white crystalline powder, M. P. 240-243 C. It can berecrystallized from ethanol and ether, or methanol or acetone.

The free base, which is an oil, can be obtained from the aqueoussolution of the dihydrochloride by adding dilute sodium hydroxide orsodium carbonate solution. The base is soluble in ether, methanol,ethanol, benzene and the like, but slightly soluble in water.

EXAMPLE 2 Z-dimethylamino-G- (c-dimethylaminoethomy) benzothiazoledihydrochloride grams of 2-dimethylamino-6-hydroxy-benzothiazole weresludged with 200 cc. of chlorbenzene and 2.3 grams of sodium hydroxideflakes. 2 cc. of water were added at 90 C. and the whole was subjectedto azeotropic distillation. In this manner the dry sodium salt of2-dimethylamino- S-hydroxy-benzothiazole was obtained. All of the saltthus formed was reacted with seven grams of1-dimethylamino-2-chloroethane in the same manner as described inExample 1. There was obtained the dihydrochloride of Z-dimethylamino 6-(B-dimethylaminoethoxy) benzothiazole in the form of white, sandycrystals, M. P. 228-231 0., when crystallized from methanol and acetone.The dihydrochloride is very soluble in water, soluble in ethanol andmethanol, but insoluble. in acetone.

EXAMPLE; 3

2-dimethylamino-6-(B-dimethylaminoiso propomy) -benzothiazoledihydrochloride All of the sodium salt, made in the same way asdescribed in Example 2 from 10 grams of2-dimethylamino-6-hydroxy-benzothiazole and 2.3 grams of sodiumhydroxide flakes in 200 cc. of chlorbenzene, was reacted with sevengrams of 2-chloro-l-dimethylamino-propane for three hours at ISO-133 C.in the same manner as described in Example 1. The 2-dimethylamino-6-(B-dimethylamino-isopropoxy) -benzothiazole dihydrochloride obtainedformed white crystals, M. 124 C. when crysta lized from ethanol andacetone. It was very soluble in water and soluble in ethanol andmethanol. The free base can be obtained by treating the dihydrochloridewith dilute sodium hydroxide or sodium carbonate solution.

6 EXAMPLE 4 2 dimethylamino 6 -(3-diethylamino-2',.2-dimethyl-propoazy)-benzothiazole dihydrochloride All of the dry sodium salt made from 10grams of 2- dimethylamino- 6 hydroxy benzothiazole, and 2.3 grams ofsodium hydroxide in 200 cc. of chlorbenzene, as described in Example 2,was reacted with 8 grams of 1-chloro-2,2-dimethyl-3-diethylamino-propane at 133 C. for four hours in the same manner asdescribed in Example 1. The 2-dimethylamino-6-(3-diethylamino-2',2'-dimethyl propoxy) benzothiazole dihydrochloride obtained formed whitecrystals, M. P. 131- 133 C. when crystallized from methanol and acetone.It is very soluble in water, methanol, and ethanol, but insoluble inacetone.

EXAllWPLE 5 2 dibutylmnino-d- (fi-dz'ethg/Zaminoethoxy) benzothiazoledihydrochloride 11.2 grams of Z-dibutylamino 6 hydroxybenzothiazole,1.75 grams of sodium hydroxide, 2 cc. of water and 1'75- cc. ofchlorbenzene were reacted as described in Example 1. All of the sodiumsalt of the thiazole thus formed was condensed with seven grams of1-diethylamino-2- chloro-ethane and the condensation product wasisolated with l-ICl gas as the above-entitled dihydrochloride, in themanner described in Example 1. The compound has a M. P. C. It is verysoluble in water and alcohol.

EXAMPLE 6 2- 4-morpholyl) -6- (,S-diethylaminoethoxy) benzothiaaole 10grams of 6-hydroxy-2-morpholyl-benzothiazole, 1.9 grams of sodiumhydroxide flakes, 2 cc. of water and 200 cc. of xylene were heated tothe boil and 50 cc. of xylene-water mixture were distilled off. Theresidue containing the sodium salt of the thiazole in xylene was reactedwith 7.5 grams of l-diethylamino-Z-chloroethane for three hours at C.The xylene was distilled ofi with steam. The residue from the steamdistillation was crystallized from methanol, yielding the free base ofthe above-entitled compound, M. P. 76 C. It forms a hydrochloride whichis very soluble in water and alcohol.

EXAMPLE 7 2- (1 miperidyl) -6- (fl-diethylaminoethoxy) benzothiazole 10grams of 6-hydroxy-2-piperidyl-benzothiazole, 1.94 grams of sodiumhydroxide flakes, 2 cc. of water and 200 cc. of chlorbenzene were heatedto the boil, and 50 cc. of chlorbenzene and water mixture were distilledofi. The residue was the sodium salt of the thiazole in chlorbenzene.Seven grams of l-diethylamino-2- chloro-ethane were then added to theresidue at 80 C. and the mixture refluxed for three hours. Thechlorbenzene was removed by steam distillation. The residue wascrystallized from methanol. It formed white needles, M. P. 68 C. Thecompound is very soluble in dilute hydrochloric acid, forming thehydrochloride of the above-entitled compound.

EXAMPLE 8 2-tetmhydroqui7zolyl-6- (p-diethylaminoethorylb'enzothz'azoledihydrochloride In the manner described in Example 1, 8.5 grams of 6hydroxy 2 tetrahydroquinolylbenzothiazole, 1.35 grams of sodiumhydroxide, 1.5 cc. of water, and 200 cc. of chlorbenzene were reacted toform the sodium salt of the thiazole, and all of the salt formed wasreacted with 4.5 grams of 1-diethylamino-2-chloro-ethane. Thecondensation product was isolated as a white crystalline powder in theform of the above-entitled dihydrochloride, and when recrystallized frommethanol and ether, had a M. P. of 150 C. with decomposition. It issoluble in water and alcohol.

EXAMPLE 9 2 methylphenylamino 6 (b dimethylaminoethoaty) benzothia2olemonohydrochlorz'de In the same manner as described in Example 1, 11grams of 6-hydroxy-2-methylphenylaminobenzothiazole, 1.85 grams ofsodium hydroxide flakes, 2 cc. of water, and 200 cc. of chlorbenzenewere reacted to form the sodium salt of the thiazole, and all of thesalt formed was reacted with 9 grams of 1-diethylamino-2-chloro-ethane.The condensation product was isolated as the above-entitledhydrochloride, M. P. 161 C. When recrystallized from methanol and ether,it formed white crystals which were soluble in water and alcohol.

EXAMPLE 1O 2 benzylmethylamino 6 (/3 diethylaminoethoscy) -benzothiazoledthydrochloride Following the procedure of Example 1, 11 grams of6-hydroxy-2-benzylmethylaminobenzothiazole, 1.8 grams of sodiumhydroxide flakes, 2 cc. of water and 200 cc. of chlorbenzene werereacted to form the sodium salt of the thiazole, and all of the saltformed was reacted with l-diethylamino-2-chloro-ethane. The condensationproduct was isolated with hydrogen chloride. The above-entitled compoundthus obtained is a crystalline grayish powder very soluble in Water,which when recrystallized from methanol and acetone has a M. P. of 116C.

In the above Examples 1-10, potassium hydroxide or lithium hydroxide canbe employed instead of sodium hydroxide to form the corresponding alkalimetal salt of the 6-hydroxy-2-tertiaryamino-benzothiazoles, and thesealkali salts reacted to form the2-tertiaryamino-6-(dialkylaminoalkoxy)-benzothiazoles, in the samemanner as described in the examples.

The following examples will illustrate the preparation of acid additionsalts of the Z-tertiaryamino-6 (dialkylaminoalkoxy) benzothiazoles withorganic acids.

EXAMPLE 11 Dipropionate of Z-dimethylamino-G-(fi-diethylamz'noethoazy)-benzothiazole To 29.3 grams of Z-dimethylamino-G-(B-diethylaminoethoxy)-benzothiazole were added at room temperature 15 grams of propionicacid. A clear almost colorless syrup was formed. This was thedipropionate of 2-dimethylamino-6-(,B-diethylaminoethoxy)-benzothiazole. The salt is soluble in water, alcoholand glycerine.

EXAMPLE 12 Dicaprylate .2-dimethyZamino-6-(fl-diethylaminoethoaty)-benzothiazole To 29.3 grams ofZ-dimethylamino-G-(fl-diethylaminoethoxy)-benzothiazole were added atroom temperature 29 grams of caprylic acid, whereupon the dicaprylatewas formed as a syrup which is very soluble in alcohol, but onlyslightly soluble in Water.

EXAMPLE 13 Diundecylenate of .2-dimethyZamino-6-(p-diethylaminoethomy)-benzothiazole To 29.3 grams of2-dimethylamino-6-(fl-diethylaminoethoxy)-benzothiazole were added atroom temperature 36.8 grams of undecylenic acid, whereupon theundecylenic salt was formed as a syrup. The salt is soluble in per centalcohol.

Mixed salts can also be obtained. Thus when to 29.3 grams of2-dimethylamino-6-(fi-diethylaminoethoxy) -benzothiazole were added 7.5grams of propionic acid and 18.4 grams of undecylenic acid, there wasobtained as an oil the Z-dimethylamino 6 (p diethylaminoethoxy)benzothiazole propionate-undecylenate.

We claim:

1. A compound of the class consisting of a Z-tertiaryamino6-(dialkylaminoalkoxy) -benzothiazole, which in the form of its freebase, can be represented by the following formula:

I S N L-Z wherein Z is a member of the group consisting of a piperidino,morpholino, tetrahydroquinolino and radical, R1 and R2 being members ofthe group consisting of lower alkyl, phenyl and benzyl radicals, and theN atom of the Z group is attached to the 2-position of the benzothiazylnucleus, and CnHZn is a member of the group consisting of alkylene,branched alkylene and alkylidene radicals wherein n stands for aninteger from 2-5, and the acid addition salts thereof.

2. The process which comprises reacting an alkali metal salt of a2-tertiaryamino-6-hydroxybenzothiazole which can be represented by thefollowing formula:

with a dialkylaminoalkyl halide which can be represented by thefollowing formula wherein Z is a member of the group consisting of apiperidino, morpholino, tetrahydroquinolino and radical, R1 and R2 beingmembers of the group consisting of lower alkyl, phenyl and benzylradicals, and the N atom of the Z group is attached to the 2-position ofthe benzothiazyl nucleus, and CnHZn is a member of the group consistingof alkylene, branched alkylene and alkylidene radicals wherein n standsfor an integer from 2-5.

3. The process according to claim 2 where the dialkylaminoalkyl halideis a. dialkylaminoalkyi chloride.

4. 2-tetrahydroquinolyl 6 (p diethylaminoethoxy) -benzothiaz01e.

5. Z-dimethylamino 6 (B-dimethylaminoethoxy) -benzothiazole.

6. 2-(1-piperidyl) -6-(5 diethy1aminoethoxy)- benzothiazole.

7. The process which comprises reacting6-hydroxy-Z-tetrahydroquinolyl-benzothiazole sodium salt with1-diethy1amino-2-chloro-ethane so as to producez-tetrahydroquinolyl-(i-(fl-diethylaminoethoxy) -benzothiazo1e.

8. The process which comprises reacting 2-dimethylamino 6hydroxy-benzothiazole sodium salt with 1-dimethylamino-2-ch1oro-ethaneso as to produce 2-dimethylamino 6 (p-dimethylaminoethoxy)-benzothiaz0le.

9. The process which comprises reacting6-hydroxy-2-piperidy1-benzothiazole sodium salt with1-diethylamino-2-chloro-ethane so as to produce 2-(1-piperidy1) -6- (f)diethylaminoethoxy) -benzothiazole.

l0. 2-dimethy1amino 6 (fl-diethylaminoethoxy) -benzothiazole.

11. 2-dimethylamino 6 (p-diethylaminoethoxy) -benzothiazoledihydrochloride.

12. The process which comprises reacting 2-dimethylamino-G-hydroxybenzothiazole sodium salt with 1-ch1or0-2-diethylamino-ethane so as toform Z-dimethylamino-G-(B diethylaminoethoxy) -benzothiazole.

NORBERT STEIGER. OSCAR KELLER.

REFERENCES CITED The following references are of record in the file ofthis patent:

FOREIGN PATENTS Number Country Date 306,590 Great Britain Feb. 25, 1929154,655 Switzerland Aug. 1, 1932

1. A COMPOUND OF THE CLASS CONSISTING OF A 1-TERTIARYAMINO -6-(DIALKYLAMINOALKOXY) -BENZOTHIAZOLE, WHICH IN THE FORM OF ITS FREEBASE, CAN BE REPRESENTED BY THE FOLLOWING FORMULA: